Study: Majority of the immune cells that protect the brain and spinal cord originate in the skull

Brain and Spinal Chord

The Washington University School of Medicine’s researchers discovered that the majority of the immune cells that protect the brain and spinal cord originate in the skull. The discovery paves the way for the development of therapies that specifically target these cells in order to prevent or treat brain disorders.

The immune system is the brain’s most dangerous adversary. It protects the brain from infection and aids in the healing of injured tissues, but it also contributes to autoimmune diseases and inflammation, which contributes to neurodegeneration.

Two new mouse studies suggest that the ambiguous nature of the immune system’s relationship with the brain may be due to the origins of the immune cells patrolling the meninges, the tissues that surround the brain and spinal cord.

Two teams of researchers at Washington University School of Medicine in St. Louis discovered unexpectedly that many of the immune cells in the meninges originate in the skull’s bone marrow and migrate to the brain via special channels without passing through the blood.

These immune cells derived from the skull serve as peacekeepers, dedicated to preserving a healthy status quo. The other immune cells, those that enter the body via the bloodstream, appear to be the culprits.

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They bear genetic signatures that indicate their proclivity to promote autoimmunity and inflammation, and their abundance increases with age or in the presence of disease or injury. Taken together, the findings illuminate a critical aspect of the brain-immune system connection that may aid in our understanding of a wide variety of brain disorders.

“There has been a knowledge gap that applies to almost every neurological disease: neuro-COVID, Alzheimer’s disease, multiple sclerosis, and brain injury, to name a few,” said Jonathan Kipnis, PhD, the Alan A. and Edith L. Wolff Distinguished Professor of Pathology and Immunology and a BJC Investigator. Kipnis is one of the papers’ senior authors. “We were aware that immune cells played a role in neurological disorders, but where did they come from? What we’ve discovered is that there is a previously unknown source for these cells.”

Kipnis demonstrated earlier this year that immune cells stationed in the meninges keep an eye on the brain. As part of these new studies, Kipnis and Marco Colonna, MD, the Robert Rock Belliveau, MD, Professor of Pathology and senior author on the other paper, launched independent investigations into the origins of these cells.

Colonna concentrated on the adaptive arm of the immune system, while Kipnis concentrated on the innate arm. Innate immune cells cause inflammation, which aids in infection defence and wound healing, but can also cause tissue damage and contribute to degenerative diseases such as Alzheimer’s and Parkinson’s disease.

While adaptive immune cells are capable of specifically targeting pathogens such as viruses and tumours, they can also mistakenly target healthy tissues in the body, resulting in autoimmune diseases such as multiple sclerosis.

Colonna and colleagues — including co-first authors Simone Brioschi, PhD, a postdoctoral researcher, Wei-Le Wang, PhD, a postdoctoral researcher, and Vincent Peng, a graduate student — tracked the development of B cells, the adaptive immune system’s antibody-producing cells.

They discovered that the majority of B cells in the meninges originated and matured in the bone marrow of the skull. As B cells mature, they must be taught to differentiate between normal body proteins that pose no threat and foreign proteins that indicate infection or disease and necessitate a response. The skull is an ideal location for B cells destined to patrol the boundaries of the central nervous system.

“B cells in the skull’s bone marrow interact with and are educated by the central nervous system,” Colonna, who is also a professor of medicine, explained. “That would not occur if they were injected directly into the bloodstream. They develop tolerance for brain proteins as a result of their direct contact with the brain.”

Along with the tolerant B cells derived from the skull, the researchers identified a population of B cells that enter the meninges via the bloodstream. These B cells derived from blood are not programmed to ignore proteins found in the central nervous system.

Colonna explained that some of these cells may mistakenly identify harmless central nervous system proteins as foreign and produce antibodies against them. Additionally, the number of these blood-derived B cells increases with age, which may help explain why the risk of neuro-immune disorders is higher in older adults.

Meanwhile, Kipnis’ team — led by graduate student Andrea Cugurra, visiting researcher Tornike Mamuladze, MD, and postdoctoral researcher Justin Rustenhoven, PhD — was examining the source of meningeal myeloid cells, a type of innate immune cell. They discovered that myeloid cells originated in the bone marrow of the skull and spinal vertebrae and entered the meninges via direct bone channels.

Kipnis and colleagues discovered that myeloid cells swarm into the brain and spinal cord in response to injury or disease using mouse models of multiple sclerosis and brain and spinal cord injuries.

The majority of entering cells are drawn from the meningeal resident population of myeloid cells. These are skewed toward immune response regulation and modulation. However, some myeloid cells enter the body through the bloodstream and are more inflammatory, capable of causing damage if not properly controlled.

“Understanding where these cells originate and how they behave is critical for unravelling the fundamental mechanisms underlying neuro-immune interactions, which will allow us to develop new therapeutic approaches for neurological conditions associated with inflammation,” said Kipnis, who is also a professor of neurosurgery, neurology, and neuroscience.

“Because these cells are located in the skull, they are relatively accessible, which opens up the possibility of developing therapies to alter their behaviour and treat neuro-immune conditions,” he added.

source: ANI

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